Effects of periodontitis on onset and severity of IR, T2DM and organ damage Type 2 Diabetes Mellitus (T2DM) has become one of the major threats to human health and a major public health care cost in the 21st century. It is estimated that 300 million people will suffer from T2DM by 2025, approximately double the number of people affected in year 2000. This epidemic of T2DM is closely linked to an increase in obesity due to the consumption of a high-fat diet (junk food) and a sedentary life-style. It is believed that a close relationship exists between periodontitis, obesity and T2DM with chronic inflammation being the common denominator. A significant problem with investigating the relationship between these conditions is the difficulty in defining whether these associations are causal in nature since most of the studies that suggest this interrelationship between periodontitis, T2DM and obesity are based on epidemiological studies or cross sectional studies. Several prospective studies using human subjects demonstrated that treatment of periodontitis leads to improvement of glycemic conditions in T2DM subjects. However, confounding factors are difficult to control in these studies. Thus, causality between periodontitis and diabetes and obesity remains unclear. Acknowledging the difficulty in human studies, we have used an animal model system in which we can induce periodontitis and monitor its systemic consequences. In our preliminary study, we induced periodontitis with plaque-retentive ligatures in female Zucker Diabetic Fatty (ZDF) rats. Non-ligated rats were used as controls. Groups of ligated and non-ligated rats were fed a high or low fat diet. The results of the study indicate that periodontitis accelerates the onset of insulin resistance (IR) in rats fed a high fat diet. The aim of this proposal is to confirm and extend our pilot studies and determine the effect of periodontitis on the onset of IR and diabetes and the severity of diabetic complications in the retina, aorta and pancreas. We will also determine temporal changes in level of selected cytokines and adipokines that have been implicated in the pathogenesis of periodontitis, T2DM and obesity using cytokine arrays. The long-term goals of my laboratory are to 1) identify the mechanism(s) by which periodontitis influences IR, T2DM and organ damage, 2) provide insights into changes in cytokine profiles during the progression through IR to T2DM that will enable clinicians to screen prediabetic individuals at risk of developing T2DM and 3) develop a paradigm in which treatment of periodontal inflammation is included as part of the comprehensive treatment plan to prevent conversion from prediabetes (IR) to T2DM. PUBLIC HEALTH RELEVANCE: Type 2 Diabetes Mellitus (T2DM) has serious complications and has become one of the major threats to human health and also a major health care cost concern for the 21st century. Epidemiological, cross and prospective studies have suggested a strong association between periodontitis and T2DM. However, no studies have demonstrated a cause and effect relationship. The current study will use an animal model system to show that periodontitis accelerates the onset and severity of prediabetes, T2DM and associated organ damage.